1. Technical Field
The present invention belongs to the field of crystal forms of compounds, and specifically relates to a crystal form of (6S)-5-methyltetrahydrofolate salt and methods for preparing the same and uses of the same.
2. Related Art
The crystal forms of active pharmaceutical ingredients are closely associated with the biological activity, bioavailability, dissolution, stability, and shelf life thereof. Therefore, during the research and development of new drugs, screening of crystal form is one of the most important tasks. Even if the drug has been on the market for many years, seeking more effective crystal forms of the drug is still the goal intensely pursued by pharmaceutical companies.
5-methyltetrahydrofolic acid was first separated from a horse liver in the form of barium salt by Donaldson et al. in 1959 and was named as Prefolic-A, and was synthesized by a chemical method in 1961 (K. O. Donaldson et al., Fed. Proc, (1961), 20, 453).
The 5-methyltetrahydrofolic acid molecule has two chiral carbon atoms, where the configuration of the chiral carbon atom at the glutamic acid site is certain, while the chiral carbon atom at Site 6 has two configurations R and S, and therefore, 5-methyltetrahydrofolic acid has been used in the form of a diastereomeric mixture. It is reported that, the two isomers have different effects with in vivo enzymes, where the compound with S configuration of the carbon atom at site 6 exhibits good efficacy, while the compound with R configuration of the carbon atom at site 6 almost has no efficacy in comparison.
The chemical name of (6S)-5-methyltetrahydrofolic acid is (6S)—N[4-[[(2-amino-1,4,5,6,7,8-hexahydro-4-oxo-5-methyl-6-pteridinyl)methyl]amino]benzoyl]-L-glutamic acid, referred to as (6S)-5-MTHF for short hereinafter. The structural formula is shown in Formula 1:

(6S)-5-MTHF and salts thereof are very unstable and easily degraded, and especially are highly sensitive to oxygen and moisture (A. L. Fitzhugh, Pteridines 1993, 4(4), 187-191). In the air, (6S)-5-MTHF and salts thereof are easily oxidized into 5-methyldihydrofolic acid and/or folic acid and the like. Therefore, it is difficult to prepare high-purity and high-stability bulk pharmaceutical chemicals or food additives, to meet the quality standards.
Due to the physical and chemical properties of (6S)-5-MTHF, it is difficult to prepare a stable crystal form of (6S)-5-MTHF by a conventional crystallization process. In the past few decades of production of (6S)-5-MTHF and preparation of formulations thereof, a reducing agent, for example, Vitamin C or 2-mercaptoethanol, is often added to achieve the purpose of anti-oxidation.
Patent Document U.S. Pat. No. 5,223,500 reports a process for preparing a stable crystal form of (6S)-5-MTHF calcium salt. The process includes the following steps: first, preparing amorphous (6S)-5-MTHF calcium salt, then transferring into boiling water of 100° C. to form a solution, cooling and standing overnight at room temperature. The collected solid is called to be a stable crystal product. However, relevant crystal parameters are not reported in this patent.
Patent Document U.S. Pat. No. 6,441,168 discloses a crystal form of (6S)-5-MTHF calcium salt with extremely high stability and a method for preparing the same. (6S)-5-MTHF sodium salt and calcium chloride are subjected to heat treatment in a polar solvent at about 90° C. to obtain four stable crystal forms of (6S)-5-MTHF calcium salt, which are respectively Form I having 2θ values of 6.3, 13.3, 16.8, and 20.1, Form II having 2θ values of 5.3, 6.9, 5.7, and 21.1, Form III having 2θ values of 6.8, 10.2, 15.4, and 22.5, and Form IV having 2θ values of 6.6, 15.9, 20.2, and 22.5.
Patent Document WO2008144953 discloses a process for preparing a stable amorphous (6S)-5-MTHF calcium salt, in which a crystal form of (6S)-5-MTHF is used as a raw material, calcium chloride is added for slow crystallization. The whole crystallization process in this patent is very complex, and the crystallization time is 16 to 18 hours, thereby reducing the production capacity in the product procedure.